Non-melanoma skin cancers (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are the most common forms of human cancer with more than 5 million cases diagnosed in the US each year. The incidence of NMSC has increased 200% over the past three decades in the US and half of all adults who live to age 65 will develop skin cancer at least once. It is widely accepted that sunlight-derived ultraviolet radiation (UVR) and advanced age are the major risk factors for NMSC. Thus NMSC incidence is 50 to 300 times higher in adults aged 75 and older compared to those under 45 years of age. Approximately, 90% of NMSC in humans are associated with exposure to sunlight-derived UVR and the major carcinogenic components of solar UVR include UVB (290-320nm) and UVA (320-400nm). Mouse models such as SKH-1 hairless mice have been studied extensively using experimental platforms that mimic exposure to these wavelengths and have facilitated our understanding of the acute and chronic effects of UVR skin damage at the cellular and molecular level. However, the impact of aging per se and its influence on susceptibility to UVR-induced NMSC has been largely overlooked by the research community, likely due to the unavailability of older animals as well as the high costs and time associated with housing animals at ages of 2 years or greater. It is our belief that in vivo skin cancer studies conducted in young mice are unlikely to address the pathogenesis of environmentally-induced human skin cancer. As such, our severe lack of understanding of age-related alterations of skin structure and function and their impact on tumor susceptibility represents a key gap in the skin cancer field. This UH2/UH3 application aims to address this key gap by testing the hypothesis that Aged murine skin is more susceptible to UVR- induced skin damage and NMSC compared to young adult skin. To test our hypothesis, we will employ SKH- 1 and Ptch1+/-/SKH-1 mice, which are well established pre-clinical models for UVR-induced SCC and BCC, respectively. During the UH2 phase, we will establish cohorts of young and aged SKH-1 and Ptch1+/-/SKH-1 mice for UVR studies as well as experimental benchmarks for UVR-induced skin defects in young and aged mouse skin. During the UH3 phase, we will conduct chronic and acute UVR studies to determine whether age impacts susceptibility to UVR-induced skin defects and NMSC. It is our belief that our SKH-1 and Ptch1+/-/SKH- 1 models will firmly establish clinical relevance for UVR-induced NMSC studies in aged mice and impact the cancer field by signifying a need to shift mechanism- and therapeutic-based research to aged mouse models in order to more closely approximate the history of sun exposure and its consequences in the human population and to better identify novel targeted therapies for age-related NMSCs.